One pivotal mediator of prostate carcinogenesis is the androgen receptor (AR) pathway. The majority of prostate cancers initially require androgens for growth, and the elimination of testosterone by surgical or chemical castration leads to marked tumor regression through a mechanism of programmed cell death. The manipulation of the androgen-receptor pathway has been used in clinical medicine since the 1940's as the primary treatment of advanced prostate cancer. However, this therapy is palliative and eliminates the potential beneficial effects of androgen-induced cellular differentiation. Surviving cancer cells lose their dependency on androgens over time and are capable of growth in the absence of serum testosterone. The molecular events leading to androgen independence (AI) have not been defined, but potential mechanisms include over expression of the AR, mutations in the AR gene leading to promiscuous ligand binding, and the activation of the AR or downstream regulatory molecules by other growth factors. This proposal will test the hypothesis that specific genes and their cognate proteins downstream of the Androgen Receptor modulate the proliferative, anti-apoptotic, and differentiation effects of the AR in neoplastic prostate epithelial cells. The broad objectives of this proposal are to define these factors, and determine their mechanism(s) of action. This hypothesis will be tested by completing the following specific aims: Aim 1: Identify the network of genes directly or indirectly regulated by the Androgen Receptor in the normal and neoplastic human prostate and in mouse models of prostate carcinoma; Aim 2: Determine the effects of specific androgen-regulated genes on the programs of prostate differentiation, apoptosis, and proliferation, and to ascertain if augmenting or inhibiting the expression of specific androgen-regulated genes influences the growth of prostate carcinoma cells; Aim 3: Determine if specific androgen-regulated genes are involved in mouse prostate development and carcinogenesis.